DREAM On, DREAM Off: A Review of the Estrogen Paradox

It is generally assumed that all estrogen receptor positive (ER+) breast cancers proliferate in response to estrogen and therefore examples of estrogen-induced regression of ER+ cancers are paradoxical. This review reexamines the estrogen regression paradox for the Luminal A subtype of ER+ breast cancers. The proliferative response to estrogen is shown to depend on the level of ER. Mechanistically, a window of opportunity study of pre-operative estradiol suggested that with higher levels of ER, estradiol could activate the DREAM-MMB (Dimerization partner, Retinoblastoma-like proteins, E2F4, and MuvB – MYB-MuvB) pathway to decrease proliferation. The response of breast epithelium and the incidence of breast cancers during hormonal variations that occur during the menstrual cycle and at the menopausal transition respectively suggest that a single hormone, either estrogen, progesterone or androgen could activate the DREAM pathway leading to reversible cell cycle arrest. Conversely, the presence of two hormones, could switch the DREAM-MMB complex to a pro-proliferative pathway. Using publicly available data, we examine the gene expression changes after aromatase inhibitors and ICI 182,780 to provide support for the hypothesis. This review suggests that it might be possible to integrate all current hormonal therapies for Luminal A tumors within a single theoretical schema.